Ubiquitination serves as a crucial posttranslational modification that governs protein turnover, signaling pathways, and the maintenance of cellular homeostasis. This intricate process is facilitated by a series of enzymatic reactions involving E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases, which provide specificity for substrate recognition. The nature of the ubiquitin chain formed can determine the fate of proteins, directing them towards proteasomal degradation, altering their functional activity, or promoting autophagic degradation. Disruption of this regulatory system is associated with a range of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). These conditions are marked by the accumulation of misfolded and aggregated proteins, which overwhelm the protein quality control systems, including the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. In the case of PD, mutations in the E3 ligase Parkin and the ubiquitin kinase PINK1 hinder mitophagy, leading to mitochondrial dysfunction and subsequent neuronal degeneration. Likewise, in HD, the presence of mutant huntingtin proteins allows for the evasion of degradation, resulting in the formation of toxic aggregates. Targeting the ubiquitination pathways emerges as a promising therapeutic strategy for addressing neurodegenerative diseases. Current research is focused on modulating E3 ligase activity, enhancing proteasomal degradation, and promoting autophagic clearance. Furthermore, the inhibition or activation of deubiquitinating enzymes (DUBs) presents additional potential strategies for restoring proteostasis. Nonetheless, significant challenges persist, particularly regarding the specificity of these therapeutic approaches. This chapter delves into the molecular mechanisms underlying ubiquitination, its implications in neurodegenerative diseases, and the development of novel therapeutic strategies, emphasizing the promise of ubiquitin-targeted therapies in meeting the clinical challenges posed by neurodegeneration.